Skin cancers are the most frequent cancers in the United States and are a significant public health problem. Basal cell carcinomas (BCCs), squamous cell carcinomas (SCCs) and malignant melanomas (MMs) are respectively, the most common types of skin cancer. The most efficacious treatment for cutaneous BCCs, SCCs and MMs is surgical excisions of tumors coupled with histological techniques to demarcate the tumor margins. However, histology for demarcation of tumor margins can be ambiguous. Furthermore, metastasis of cancer cells to distant sites are not detected. Optical imaging in concert with fluorescent probes that bind tumors may aid physicians in: a) demarcating skin tumor margins for surgical treatment, and b) identifying metastatic spread at an early and potentially curable stage of disease. Hyaluronan (HA) is a glycosaminoglycan expressed in high concentrations by nearly all BCCs, SCCs and MMs. Thus, HA may be a new molecular marker for these skin cancers. Recently, we have developed an HA-binding peptide (termed "Pep-1") that binds strongly to HA polymers associated with cutaneous melanoma tumors but weakly to HA in adjacent non-lesional skin. Based on these results we propose to test the utility of fluorescently labeled Pep-1 in concert with near-infrared multi-photon microscopy to image cutaneous BCCs, SCCs and MMs in murine models (Aim 1). Briefly, we will determine the optimal Pep-1 concentrations and post injection time intervals for near-infrared microscopic imaging using human tumor xenograft models. Next, we will examine the utility of optimized Pep-1 concentrations and post injection time intervals to demarcate tumor margins in mice that spontaneously develop BCC tumors or mice that develop skin lesions after photocarcinogenesis (SCC and MM models). Because metastasis of MMs and SCCs can result in death early detection of disseminated disease for therapeutic intervention can save lives. Thus, we will also assess the potential utility of fluorescently labeled Pep-1 in concert with near-infrared wavelengths and a CCD (charge coupled device) camera to detect metastatic disease (Aim 2). Again, we will determine the optimal concentrations for Pep-1 and the post injection time interval for detecting systemic disease using human tumor xenograft models. Once we have determined the optimal Pep-1 concentrations and time-to-imaging we will examine the utility of Pep-1 to detect spontaneous MM metastasis in mice.